UMR788 INSERM et Université Paris-Sud, Bátiment Grégory Pincus, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicětre Cedex, France.
Eur J Neurosci. 2013 Feb;37(3):366-79. doi: 10.1111/ejn.12074. Epub 2012 Nov 29.
Hypoglossal motoneurons (HMs) are known to be under 'permanent' bicuculline-sensitive inhibition and to show 'transient' synaptic γ-aminobutyric acid (GABA)(A) and glycine inhibitory responses. The present paper describes a permanent bicuculline-sensitive current that should contribute to their tonic inhibition. This current was recorded in brainstem slices superfused without any exogenous agonist and remained detectable with tetrodotoxin. It could also be blocked by the other GABA(A) antagonists picrotoxin (PTX) and 2-(3-carboxypropyl)-3-amino-6-(4 methoxyphenyl)pyridazinium bromide) (SR95531; gabazine), but persisted in the presence of a specific blocker of α5-containing GABA(A) receptors. Addition of 2 μm 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP), known to preferentially activate GABA(A) receptors devoid of a γ-subunit, induced a sustained anionic current that could be further enhanced by neurosteroids such as allopregnanolone (100 nm). Thus, HMs show a tonic inhibitory current carried by extrasynaptic γ-free GABA(A) receptors, highly sensitive to neurosteroids. A second result was obtained by using SR95531 at concentrations sufficiently high to rapidly block the tonic current above the chloride equilibrium potential (E(C) (l)). Surprisingly, below E(C) (l) , SR95531 (10-40 μm) activated a sustained inward current, associated with a conductance increase, and resistant to bicuculline or PTX (100 μm). Similarly, after blockade of the bicuculline-sensitive current, SR95531 activated an outward current above E(C) (l). The bicuculline-resistant anionic current activated by SR95531 could be blocked by a GABA(C) receptor antagonist. Thus, two types of inhibitory GABA receptors, belonging to the GABA(A) and GABA(C) families, are able to show a sustained activity in HMs and provide promising targets for neuroprotection under overexcitatory situations known to easily damage these particularly fragile neurons.
舌下运动神经元（HMs）已知受到“永久”的bicuculline 敏感抑制，并表现出“瞬态”的突触γ-氨基丁酸（GABA)(A）和甘氨酸抑制反应。本文描述了一种应有助于其紧张抑制的永久性 bicuculline 敏感电流。该电流在无任何外源性激动剂的脑片切片中记录，并在存在河豚毒素时仍可检测到。它也可以被其他 GABA(A)拮抗剂胡椒碱（PTX）和 2-（3-羧基丙基）-3-氨基-6-（4-甲氧基苯基）哒嗪翁溴化物（SR95531；gabazine）阻断，但在存在特定的α5 包含 GABA(A)受体阻断剂的情况下仍持续存在。添加 2 μm 4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇盐酸盐（THIP），已知优先激活无γ-亚基的 GABA(A)受体，诱导持续的阴离子电流，该电流可被神经甾体如孕烷醇酮（100nm）进一步增强。因此，HMs 显示出一种由突触外无γ-GABA(A)受体携带的紧张抑制电流，对神经甾体高度敏感。第二个结果是通过在足以快速阻断氯离子平衡电位（E(C) (l)）上方的紧张电流的高浓度下使用 SR95531 获得的。令人惊讶的是，在 E(C) (l) 以下，SR95531（10-40μm）激活了一种持续的内向电流，与电导增加相关，并对 bicuculline 或 PTX（100μm）具有抗性。同样，在阻断 bicuculline 敏感电流后，SR95531 在 E(C) (l) 上方激活外向电流。SR95531 激活的bicuculline 抗性阴离子电流可被 GABA(C)受体拮抗剂阻断。因此，两种类型的抑制性 GABA 受体，属于 GABA(A)和 GABA(C)家族，能够在 HMs 中表现出持续的活性，并为在已知容易损伤这些特别脆弱神经元的过度兴奋情况下的神经保护提供有希望的靶点。
